Benzylidene hydrazino-1,2,4-triazoles, pharmaceuticals therewith, and method of use

ABSTRACT

Compounds having the general formula ##STR1## pharmaceutical preparations containing the compounds and use in the treatment of hypertension.

This invention relates to new triazoles and methods for theirpreparation. The invention also relates to the preparation ofpharmaceutical preparations containing the triazoles and to methods forthe pharmacological use of the triazoles.

PRIOR ART

Hypotensive agents have been known for a considerable time. It has alsobeen known that these agents exert their effects through differentmechanisms of action. Side-effects which have clinical implications ofmajor importance are frequently encountered among these compounds. Awell-known example is a rise in the blood pressure of shorter or longerduration after administration and before the onset of the desired fallin blood pressure. A further example is the sedative effect of theseagents which may make these agents unsuitable for use by persons whoperform any form of task which requires alertness, for instancecar-driving.

OUTLINE OF INVENTION

(a) General Outline

We have found that certain compounds related to4-amino-3-benzylidenehydrazino-1,2,4-triazoles have the ability oflowering the arterial blood pressure of unanesthetized animals withexperimentally induced hypertension in oral doses which do not producesedation or other apparent untoward effects.

More particular, these compounds have the general formula ##STR2##wherein R¹, R² and R³ are the same or different and each represents ahydrogen atom, a lower alkyl group or a halogen atom, R⁴ represents ahydrogen atom, a lower alkyl group or a pyridyl group, R⁵, R⁶, R⁷ and R⁸are the same or different and each represents a hydrogen atom or a loweralkyl group, provided that R⁴ is a lower alkyl group or a pyridyl groupwhen R¹, R² and R³ are hydrogen atoms and that R⁶, R⁷ and R⁸ do notsimultaneously represent a hydrogen atom.

The invention also comprises pharmaceutically acceptable salts of thecompounds of the formula I.

Illustrative examples of radicals included in the above definitions are

pyridyl group: 2-pyridyl

lower alkyl group: methyl, ethyl, n-propyl and iso-propyl

halogen atom: chlorine, bromine, iodine and fluorine.

By the expression "lower alkyl group" in this application is to beunderstood alkyl groups with 1, 2 or 3 carbon atoms.

The table below gives some compounds within the scope of thisapplication

    ______________________________________                                         ##STR3##                                                                     R.sup.1                                                                              R.sup.2   R.sup.3  R.sup.6                                                                              R.sup.7                                                                              R.sup.8                               ______________________________________                                        2-Cl   6-Cl      H        CH.sub.3                                                                             H      H                                     2-Cl   6-Cl      H        CH.sub.3                                                                             CH.sub.3                                                                             H                                     2-Cl   6-Cl      H        CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                              2-Cl   6-Br      H        H      CH.sub.3                                                                             H                                     2-Cl   6-Br      H        CH.sub.3                                                                             CH.sub.3                                                                             H                                     2-Cl   6-Br      H        CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                              2-Cl   6-Cl      4-CH.sub.3                                                                             CH.sub.3                                                                             H      H                                     2-Cl   6-Cl      4-CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                             H                                     2-Cl   6-Cl      4-CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                              2-Cl   6-CH.sub.3                                                                              4-Cl     CH.sub.3                                                                             H      H                                     2-Cl   6-CH.sub.3                                                                              4-Cl     CH.sub.3                                                                             CH.sub.3                                                                             H                                     2-Cl   6-CH.sub.3                                                                              4-Cl     CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                              ______________________________________                                    

(b) Pharmaceutical preparations

In clinical practice the compounds of the present invention willnormally be administered orally, rectally or by injection, in the formof pharmaceutical preparations comprising the active ingredient eitheras a free base or as a pharmaceutically acceptable non-toxic, acidaddition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate,sulphate, sulphamate, and the like, in association with apharmaceutically acceptable carrier. Accordingly, terms relating to thenovel compounds of this invention whether generically or specificallyare intended to include both the free amine base and the acid additionsalts of the free base, unless the context in which such terms are used,e.g. in the specific examples would be inconsistent with the broadconcept. The carrier may be a solid, semisolid or liquid diluent orcapsule. These pharmaceutical preparations constitute a further aspectof this invention. Usually the active substance will constitute between0.1 and 95% by weight of the preparation, more specifically between 0.5and 20% by weight for preparation intended for injection and between 2and 50% by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compound of theinvention in the form of dosage units for oral application, the selectedcompound may be mixed with a solid pulverulent carrier, e.g. lactose,saccharose, sorbitol, mannitol, starches such as potato starch, cornstarch or amylopectin, cellulose derivatives, or gelatine, and alubricant such as magnesium stearate, calciumstearate, polyethyleneglycol waxes, and the like, and then compressed to form tablets. Ifcoated tablets are required, the cores, prepared as described above, maybe coated with a concentrated sugar solution which may contain e.g. gumarabic, gelatine, talcum, titanium dioxide, and the like. Alternatively,the tablet can be coated with a lacquer dissolved in a readily volatileorganic solvent or mixture of organic solvents. Dyestuffs may be addedto these coatings in order to readily distinguish between tabletscontaining different active substances or different amounts of theactive compound.

For the preparation of soft gelatine capsules (pearl-shaped closedcapsules) consisting of gelatine, and for example, glycerol or similarclosed capsules, the active substance may be admixed with a vegetableoil. Hard gelatine capsules may contain granulates of the activesubstance in combination with solid, pulverulent carriers such aslactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch,corn starch or amylopectin), cellulose derivatives or gelatine.

Dosage units for rectal application can be prepared in the form ofsuppositories comprising the active substance in admixture with aneutral fatty base, or gelatine rectal capsules comprising the activesubstance in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing from about 0.2% to about20% by weight of the active substance herein described, the balancebeing sugar and a mixture of ethanol, water, glycerol, andpropyleneglycol. Optionally such liquid preparations may containcoloring agents, flavoring agents, saccharine and carboxymethylcelluloseas a thickening agent.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance preferably in a concentration of from about 0.5% toabout 10% by weight. These solutions may also contain stabilizing agentsand/or buffering agents and may conveniently be provided in variousdosage unit ampoules.

(c) Preferred embodiment

The preferred compounds of the invention have the structural formula##STR4## wherein R⁶ is a hydrogen atom or a methyl group, R⁷ is ahydrogen atom or a methyl group and R⁸ is a hydrogen atom or a methylgroup.

The compound of the formula ##STR5## is particularly interesting.

Preferably these compounds will be prepared and used in the form oftheir hydrochloride salts.

(d) Methods of preparation

A. Generally the compounds of the formula I are prepared via thefollowing route (R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the above givendefinitions): ##STR6##

Substituted monothiocarbohydrazones of the formula IV are prepared bytreating of aldehydes or ketones of the formula II with athiocarbohydrazide of the formula III. The reaction is preferablyperformed at elevated temperatures in a suitable solvent e.g. ethanol oracetic acid. ##STR7##

The substituted monothiocarbohydrazones IV are transformed intoS-alkylisothiocarbohydrazones V by means of an halide or adialkylsulphate such as methyl iodide, ethyl iodide, dimethyl sulphate,benzyl chloride and the like.

The reaction may be conducted in solvents such as ethanol from aboutroom temperature to reflux temperature. The addition salt of V may beconverted to the free base using conventional techniques, such astreating the salt with sodium carbonate solution. ##STR8##

Alternatively, the S-alkylisothiocarbohydrazones can also be preparedfrom the corresponding aldehydes or ketones and a properly substitutedS-alkylisothiocarbohydrazide VI. The reaction is performed as for themonothiocarbohydrazones. ##STR9##

The addition salts or the free bases of theS-alkylisothiocarbohydrazones V are reacted with hydrazine orN,N-dialkylhydrazines yielding substituted1-benzylideneamino-2,3-diaminoguanidines VII. The reaction may beconducted in solvents such as alcohols or in aqueous mixtures thereof.The products may be recovered using conventional techniques, such asfiltration. The acid addition salts may be obtained from the free baseby salifying. ##STR10##

Compounds of the formula I are prepared from the substituted1-benzylideneamino-2,3-diaminoguanidines VII by reaction with carboxylicacids at elevated temperatures. The obtained4-amino-3-benzylidenehydrazino-1,2,4-triazoles of formula I arepreferably isolated as the addition salts, e.g. the hydrochlorides.

The intermediate compounds of formula III and VI are known or may beprepared according to methods disclosed in the literature.

B. Compounds of the formula I wherein R⁷ and R⁸ represent a hydrogenatom and R⁶ is an alkyl group can be prepared via the following route(R¹, R², R³, R⁴ and R⁵ have the previously given definitions): ##STR11##(Z= a N-protecting group, such as an arylsulphonyl group, analkylsulphonyl group, an acyl group or an alkoxycarbonyl group).

The amides in the scheme above are prepared from the correspondingamines. The reaction involves the acylation of the amine or amine saltwith e.g. chloroformic esters, sulphonyl halides, acyl halides or acidanhydrides. ##STR12##

The amides is treated with an alkyl halide or a dialkyl sulphate. Thereaction is preferably performed in a suitable solvent such as ethanolor water and in the presence of a base such as sodium hydrogen carbonateor sodium hydroxide. ##STR13##

In the last step hydrolysis affords the desired compounds.

(e) Working examples

This invention is further illustrated by the following examples.

EXAMPLE 14-Acetamido-3-[1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino]-1,2,4-triazolAlternative A

To a warm solution (˜ 45° C.) of 46.0 g of4-amino-3-(2,6-dichlorobenzylidenehydrazino)-1,2,4-triazolehydrochloride in 150 ml of dry pyridine is added dropwise while stirring25 ml of acetyl chloride. The mixture is stirred overnight at roomtemperature and is then poured into 1 liter of ice water. Theprecipitate formed is collected by filtration and washed with water.Yield: 43.5 g, m.p. 205°-210° .

The crude product is recrystallized from dilute dioxane yielding 31.6 gof the compound, melting at 211°-212°. Calculated for C₁₃ H₁₂ Cl₂ N₆ O₂: C 43.96, H 3.41, Cl 19.95, N 23.66, O 9.01. Found: C 44.0, H 3.43, Cl20.1, N 23.8, O 8.95.

Alternative B

To a stirred suspension of 15 g of4-diacetylamino-3-[1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino]-1,2,4-triazole in a mixture of 100 ml of ethanol and 200 ml of water isadded 50 ml of saturated sodium carbonate solution. The stirred mixtureis heated in a boiling water bath for 10 minutes. The obtained solutionis diluted with water to a volume of 1 liter and is then acidified withacetic acid. The precipitate is filtered off and washed with water.Yield: 8.1 g, m.p. 209°-211°. The crude compound is recrystallized fromdilute dioxane yielding 6.0 g of the compound, melting at 211°-212° .

4-Diacetylamino-3-[1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino]-1,2,4-triazole

A solution of 30.8 g of 4-amino-3-(2,6-dichlorobenzylidenehydrazino)-1,2,4-triazole hydrochloride in 100 ml of acetic anhydride is heated atreflux temperature for 1.5 hours. After cooling 600 ml of water isadded. The mixture is then stirred at room temperature for 2 hours. Theobtained precipitate is collected and washed with water. Yield: 35.6 g,m.p. 140°-150°. The product is recrystallized from diluted ethanol.Yield: 15.1 g, m.p. 178°-179° .

Calculated for C₁₅ H₁₄ Cl₂ N₆ O₃ ; C 45.36, H 3.55, Cl 17.85, N 21.16, O12.08 Found: C 44.9, H 4.08, Cl 17.8, N 20.9, O 12.1.

4-(N-Methylacetamido)-3-[-1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino]-1,2,4-triazole

To a solution of 31.5 g of4-acetamido-3[1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino]-1,2,4-triazole and 53.0 g of sodium carbonate in 400 ml of water isadded dropwise, while stirring and cooling in an ice bath, 40 ml ofdimethyl sulphate (2 h). After the addition the mixture was stirred for2,5 h while cooling in ice and left overnight at room temperature. Theobtained precipitate is collected and recrystallized twice fromdioxane-isopropyl ether. Yield: 7.3 g, m.p. 167°-169° .

Calculated for C₁₄ H₁₄ Cl₂ N₆ O₂ ; C 45.54, H 3.82, Cl 19.20, N 22.76, O8.67. Found: C 45.8, H 4.07, Cl 19.2, N 22.7, O 9.01.

3-(2,6Dichlorobenzylidenehydrazino)-4-methylamino-1,2,4-triazole-hydrochloride

A solution of 6.2 g of4-(N-methylacetamido-3-[1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino]-1,2,4-triazole in 50 ml of acetic acid, 50 ml of concentratedhydrochloric acid and 50 ml of water is heated at reflux overnight. Thesolution is evaporated and the residue is recrystallized fromethanol-isopropyl ether. Yield 2.4 g, m.p. 205°-207°. Two morerecrystallizations from the same solvent mixture gave 1.5 g of ananalytically pure sample, m.p. 210°-211° .

Calculated for C₁₀ H₁₀ Cl₂ N₆ HCl: C 37.34, H 3.45, Cl 33.07, N 26.13.Found: C 37.5, H 3.56, Cl 33.3, N 25.7.

EXAMPLE 2 1-[2,6-dichlorobenzylidene]-5,5-dimethyl-thiocarbohydrazine

5.4 g of 1,1-dimethylthiocarbohydrazine and 7.1 g of2,6-dichlorobenzaldehyde was refluxed in 100 ml of dry ethanol for 18hours. The reaction mixture was cooled, and the solid precipitate wasfiltered off. Yield 7.3 g. m.p. 205 °C.

1-[2,6-dichlorobenzylidene]-5,5,5-trimethylisothiocarbohydrazine

7.3 g of 1-[2,6-dichlorobenzylidene] -5,5-dimethyl-thiocarbohydrazineand 3.5 g of CH₃ I in 50 ml of dry ethanol is refluxed for 2 hours. Thereaction mixture is evaporated, ether is added and the crystallineresidue filtered. Yield 5.2 g of a low melting solid (<50° C.).

1-[2,6-dichlorobenzylidene]-2-dimethylamino-3-aminoguanidine

0.6 g of hydrazinehydrate and 5 g of 1[2,6-dichlorobenzylidene]-5,5,5-trimethylisothiocarbohydrazine weredissolved in 50 ml of dry ethanol and stirred for 18 hours. The solventis evaporated and water added. pH is adjusted to 8-10 and theprecipitate is filtered. It is then dissolved in HCl-acid, the excess ofwhich is evaporated. Yield 2.6 g. m.p. 183° C.

3-[2,6-dichlorobenzylidenehydrazino]-4-dimethylamino-1,2,4-triazole

2.5 g of 1-[2,6-dichlorobenzylidene]-2-dimethylamino-3-aminoguanidine isdissolved in 25 ml of 85% formic acid for one hour. The mixture isevaporated and the residue dissolved in 25 ml 6 N HCl-acid and refluxedfor another 30 min. The reaction mixture is evaporated and the residuerecrystallized. Yield 1 g. m.p. 189° C.

(f) Biological test

The antihypertensive effects of the hydrochloride salt of the compoundof the invention with the designation FLA 486 having the formula##STR14## have been compared with those of FLA 136 with the formula##STR15## in spontaneously hypertensive rats of the SHR/N strain(Mollegaard Hansens Avlslaboratorier A/S, Denmark). The animals wereprepared for measurements of the arterial blood pressure through acatheter implanted into the abdominal aorta and exteriorized at the baseof the neck. Groups of two rats were given three consecutive daily oraldoses of the test compounds. Measurements were performed before andthree hours after administration to the unanesthetized animal. Theeffective antihypertensive dose of FLA 486, defined as the dose whichreduced the mean arterial blood pressure more than 30 mm Hg was 5-10mg/kg. The corresponding value for FLA 136 was 5-10 mg/kg.

We claim:
 1. A compound of the formula ##STR16## or a pharmaceuticallyacceptable salt thereof wherein R¹, R² and R³ are the same or differentand each represents a hydrogen atom, a lower alkyl group or a halogenatom, R⁴ represents a hydrogen atom, a lower alkyl group, R⁵, R⁶, R⁷ andR⁸ are the same or different and each represents a hydrogen atom or alower alkyl group, provided that R⁴ is a lower alkyl group when R¹, R²and R³ are hydrogen atoms and that R⁶, R⁷ and R⁸ do not simultaneouslyrepresent a hydrogen atom.
 2. A compound according to claim 1characterized by the formula ##STR17## or a pharmaceutically acceptablesalt thereof wherein R⁶ is a hydrogen atom or a methyl group, R⁷ is ahydrogen atom or a methyl group and R⁸ is a hydrogen atom or a methylgroup.
 3. A compound according to claim 2 characterized by the formula##STR18## or a pharmaceutically acceptable salt thereof.
 4. Apharmaceutical preparation which comprises as active ingredient atherapeutically effective amount of at least one compound of the formula##STR19## or a pharmaceutically acceptable salt thereof wherein R¹, R²and R³ are the same or different and each represents a hydrogen atom,lower alky group or a halogen atom; R⁴ represents a hydrogen atom, alower alkyl group, R⁵, R⁶, R⁷ and R⁸ are the same or different and eachrepresents a hydrogen atom or a lower alkyl group, provided that R⁴ is alower alkyl group when R¹, R² and R³ are hydrogen atoms and that R⁶, R⁷and R⁸ do not simultaneously represent a hydrogen atom, in associationwith a pharmaceutically acceptable carrier.
 5. A pharmaceuticalpreparation according to claim 4 which comprises as active ingredient athereapeutically effective amount of at least one compound of theformula ##STR20## or a pharmaceutically acceptable salt thereof whereinR⁶ is a hydrogen atom or a methyl group, R⁷ is a hydrogen atom or amethyl group and R⁸ is a hydrogen atom or a methyl group, in associationwith a pharmaceutically acceptable carrier.
 6. A pharmaceuticalpreparation according to claim 5 which comprises as active ingredient atherapeutically effective amount of a compound of the formula ##STR21##or a pharmaceutically acceptable salt thereof in association with apharmaceutically acceptable carrier.
 7. A method for the treatment ofhypertension, characterized in administration to a host suffering fromsuch ailment a therapeutically acceptable amount of a compound of theformula ##STR22## or a pharmaceutically acceptable salt thereof whereinR¹, R² and R³ are the same or different and each represents a hydrogenatom, a lower alkyl group or a halogen atom, R⁴ represents a hydrogenatom, a lower alkyl group, R⁵, R⁶, R⁷ and R⁸ are the same or differentand each represents a hydrogen atom or a lower alkyl group, providedthat R⁴ is a lower alkyl group when R¹, R² and R³ are hydrogen atoms andthat R⁶, R⁷ and R⁸ do not simultaneously represent a hydrogen atom.
 8. Amethod according to claim 7 characterized in the administration of acompound of the formula ##STR23## or a pharmaceutically acceptable saltthereof wherein R⁶ is a hydrogen atom or a methyl group, R⁷ is ahydrogen atom or a methyl group and R⁸ is a hydrogen atom or a methylgroup.
 9. A method according to claim 8, characterized in theadministration of a compound of the formula ##STR24## or apharmaceutically acceptable salt thereof.